1. Field of the Invention
The present invention generally relates to the fields of molecular biology and medicine. More particularly, it concerns the identification of compounds that inhibit Wnt-mediated signal transduction pathways, through interactions with the porcupine protein.
2. Description of Related Art
The evolutionary elaboration of gene families in complex multicellular animals provides diverse instructive cellular cues based on single signaling modalities and safeguards against genetic insults. During development, members of the Wnt family of signaling molecules—nineteen in all—contribute to almost all aspects of vertebrate development through induction of unique and shared cellular responses (Angers and Moon, 2009; van Amerongen and Nusse, 2009). In post-embryonic animals, their functions are essential to homeostatic tissue renewal and regeneration (Reya and Clevers, 2005). Previous work has lead to the development of inhibitors of the Wnt pathway and shown that the inhibitors' physiological target is Porcupine (Porcn), a membrane-bound O-acyltransferase (MBOAT) family protein (Chen et al., 2009; Yang et al., 2008). This acyltransferase catalyzes the palmitoylation of Wnt enabling its exit from the secretory pathway and subsequent activation of cellular responses. Compromised Porcn activity commonly results in developmental disorders including focal dermal hypoplasia (Goltz syndrome) whereas hyperactivity of Porcn is associated with cancerous cell growth (Che, et al., 2008) The inhibition of Porcn is envisioned to be an effective strategy for broadly suppressing Wnt signaling and thus hold potential in regenerative medicine and anti-cancer applications. Although genetically based targeting of Wnt signaling components suggests that chemical inhibitors of Wnt signaling may give rise to toxic effects, Porcn inhibitors have proven to be remarkably non-toxic in rodents (Proffitt et al., 2013).
Accordingly, identification of methods and compounds that modulate the Wnt-dependent cellular responses may offer an avenue for therapeutic treatment of diseases associated with aberrant activity of these pathways.